title: mTORC1/2 targeted by n-3 polyunsaturated fatty acids in the prevention of mammary tumorigenesis and tumor progression.
abstract: Although epidemiological and preclinical studies have shown the preventative effects of n-3 polyunsaturated fatty acids (PUFAs) on breast cancer, inconsistencies still remain in the data and the underlying mechanisms remain unclear. In this study, we identified mammalian target of rapamycin (mTOR) signaling, which plays an essential role in cell proliferation and breast tumorigenesis, as a target of n-3 PUFAs. In breast cancer cell lines, n-3 PUFAs rapidly and efficiently suppress both mTOR complex 1 (mTORC1) and mTORC2 and their downstream signaling, and subsequently inhibit cell proliferation and angiogenesis while promoting apoptosis. Further study indicates that stabilization of the mTOR-raptor complex by n-3 PUFAs may contribute to their inhibitory effect on mTORC1. Importantly, four complementary and well-controlled animal models were utilized to identify the role and molecular target of n-3 PUFAs in the prevention of breast carcinogenesis and progression, namely: (1) chemically induced mammary tumor rats with a high dietary intake of n-3 PUFAs; (2) nude mice implanted with mammary tumor cell lines stably expressing fat-1, a desaturase that catalyzes the conversion of n-6 to n-3 PUFAs and produces n-3 PUFAs endogenously; (3) fat-1 transgenic severe combined immune deficiency mice implanted with breast tumor cells; and (4) the fat-1 transgenic mouse mammary tumor virus-polyoma virus middle T oncogene double-hybrid mice, a model of aggressive breast cancer. In summary, dietary and endogenous n-3 PUFAs abrogate the activity of mTORC1/2 pathways in vitro and in vivo and prevent breast carcinogenesis, tumor growth and metastasis. Taken together, our findings convincingly clarify the causal relationship between n-3 PUFAs and breast cancer prevention and establish mTORC1/2 as a target of n-3 PUFAs.
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: C
authors.initials: C
authors.lastname: Jia
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: P
authors.initials: P
authors.lastname: Lai
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Song
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ren
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Gao
authors.affiliation: College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: H
authors.initials: H
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wan
authors.affiliation: Department of Anatomy and Neurobiology, Southern Medical University, Guangzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: A
authors.initials: A
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Reproductive Medicine and Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
authors.forename: X
authors.initials: X
authors.lastname: Bai
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000517:prevention & control*; D002273:Carcinogens; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D015525:Fatty Acids, Omega-3 / Q000737:chemistry*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000517:prevention & control*; D008325:Mammary Neoplasms, Experimental / Q000517:prevention & control*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008770:Methylnitrosourea / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D051381:Rats; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D015525:Fatty Acids, Omega-3; D046912:Multiprotein Complexes; D008770:Methylnitrosourea; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases